Objectives: This application defines a program to further the research career of a promising junior investigator within a mentored setting. Successful completion would allow the investigator to initiate a career as an independent clinician-scientist, conducting translational research directed at creating and evaluating therapeutics and vaccine candidates for herpes simplex virus (HSV), with the related goal of improving the understanding of immunity to HSV. The specific project for this application investigates the importance of HSV interactions with its principal entry receptors on neonatal disease and the influence of an interaction between an HSV glycoprotein and an immune signaling protein on memory immunity to HSV. Background: Herpes simplex viruses are common human pathogens, infecting more than 60% of American adults, with newborns particularly susceptible to severe disease. HSV initially infects cells after interacting with one of two principal receptors, HVEM and nectin. Prior published data suggest that neurologic disease is largely related to viral entry using nectin; our preliminary data suggest that the virus may manipulate memory immunity by engagement of HVEM. Research design and methods: In Specific Aim 1 of this project, we will prime immunity to HSV in adult female mice by intravaginal infection with attenuated HSV-2, using either wild-type virus or virus altered to abrogate binding to HVEM. We will then rigorously investigate the memory lymphocyte response after challenge with either wild-type or mutant virus, addressing the hypothesis that regulatory T-cell responses at the mucosa are altered in the memory phase by initial viral interaction with HVEM. In Aim 2, we will test the influence of HVEM engagement on neonatal HSV disease. We will use similar immunologic methods as in Aim 1 to test whether immunity in newborn mice is altered by engagement of HVEM. Routes of infection will be relevant to neonatal disease in humans. In Aim 3, we will investigate in detail our preliminary observation that HVEM is not sufficient to cause HSV disease in newborn mice, looking at spread and pathogenesis of disease in mice lacking one or both principal receptors. We will also measure the relative expression of different receptors in different tissues during early postnatal development. Research environment: The candidate proposes to develop this project within an environment with established success at nurturing the careers of junior investigators. Under the supervision of experts in the field, this project will add new expertise to the candidate's background, including development of murine neonatal infection models, investigation of newborn immune responses, and immunohistochemical methods. Career development activities within the proposal include didactic coursework in molecular biology and immunology, regular evaluations by a career advisory committee, and training in the responsible conduct of research. Public health relevance: The understanding of memory immunity to herpes simplex virus (HSV) has implications for the development of vaccines effective at preventing shedding in chronically infected individuals, and may lead to development of therapeutic methods to minimize or prevent neonatal exposure during delivery. A better understanding of the influence of different HSV receptors on pathogenesis of neonatal disease may lead to improved therapeutics in this population.